Increased Population Risk of AIP-Related Acromegaly and Gigantism in Ireland
AuthorRadian, S; Diekmann, Y; Gabrovska, P; Holland, B; Bradley, L; Wallace, H; Stals, K; Bussell, A-M; McGurren, K; Cuesta, M; ...
Source TitleHuman Mutation
University of Melbourne Author/sBalding, David
AffiliationSchool of Mathematics and Statistics
Document TypeJournal Article
CitationsRadian, S., Diekmann, Y., Gabrovska, P., Holland, B., Bradley, L., Wallace, H., Stals, K., Bussell, A. -M., McGurren, K., Cuesta, M., Ryan, A. W., Herincs, M., Hernandez-Ramirez, L. C., Holland, A., Samuels, J., Aflorei, E. D., Barry, S., Denes, J., Pernicova, I. ,... Korbonits, M. (2017). Increased Population Risk of AIP-Related Acromegaly and Gigantism in Ireland. HUMAN MUTATION, 38 (1), pp.78-85. https://doi.org/10.1002/humu.23121.
Access StatusOpen Access
The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304* ; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011-0.0047) and zero in ROI (0-0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non-Irish patients (0-2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275-5,000) years. tMRCA-based simulations predicted 432 (90-5,175) current carriers, including 86 affected (18-1,035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease.
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